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ePRO Evolution and Emerging Best Practice. Adam Wood PDSM PRO Workshop 2010. Content. Defining PROs Where are we now? Why ePRO? Obstacles Emerging Best Practice What about….? For reference. Defining PROs. Defining PROs.

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epro evolution and emerging best practice

ePRO Evolution and Emerging Best Practice

Adam Wood

PDSM PRO Workshop 2010

content
Content
  • Defining PROs
  • Where are we now?
  • Why ePRO?
  • Obstacles
    • Emerging Best Practice
  • What about….?
  • For reference

confidential

defining pros1
Defining PROs
  • “A PRO is a measurement of any aspect of a patient’s health status that comes directly from the patient” - FDA
    • Patient diaries
    • Questionnaires
    • Disease specific measures
  • ePRO is any electronic implementation
    • IVRS
    • Hardware device (e.g. PDA, tablet)
    • Digital pen

confidential

pros are all round us
PROs are all round us
  • CenterWatch estimate they are used in 75% of trials
    • Visit based measures more common that remote reported diaries
  • Some PROs are more important than others
  • Growing need for Health Economic data
    • Proving efficacy is one thing, persuading payers to fund your treatment can be quite another
    • Increasing trend to integrate Health Economics data alongside efficacy data in Ph II/III

confidential

epro is mainstream
ePRO is Mainstream
  • A number of proven vendors with strong track records
  • Best practice is well established
    • Success is vastly more likely than failure
  • Regulators are positive about PROs
    • “Some treatment effects are known only to the patient”*
  • ePRO is an integral part of PROs
    • Not a separate, special case
    • And it’s not EDC

* FDA PRO Guidance.

confidential

epro and regulators
ePRO and Regulators
  • Regulators in Europe and the US are keenly supportive of electronic PROs
    • invivodata regularly interacts with EMA and FDA
  • Drugs approved based on ePRO data worldwide
    • Japan (at least one)
    • Europe (multiple)
    • US (multiple)
  • invivodata inspected by regulators in all 3

confidential

fda pro guidance
FDA PRO Guidance
  • Finalised in 2009; drafted in 2006
    • Defines new “rules of engagement” for use of PROs
  • Questions it triggers
    • Conceptual framework
    • Application of scale to patient population
    • Patient input into PRO design
    • Reliability, validity, ability to detect change
    • Translations
    • And, oh yes….mode of administration (p or e)

confidential

fda spoke and wheel
FDA “Spoke and Wheel”*

* Figure from: Patrick DL, Burke LB, Powers JH, Scott JA, Rock EP, Dawisha S, et al. FDA Paper Draft: Patient-Reported Outcomes to Support Medical Product Labeling Claims. Value in Health 2007

confidential

fda on patient compliance

(Federal Register, Vol. 71, No. 23; Feb. 3, 2006)

FDA on Patient Compliance

“If a patient diary or some other form of unsupervised data entry is used, the FDA plans to review the protocol to determine what measures are taken to ensure that patients make entries according to the study design and not, for example, just before a clinic visit when their reports will be collected." 

(Pg. 10; 334-337 – emphasis added)

confidential

is this familiar

Missing data

Ambiguous data

Conflicting data

Extraneous data

Is This Familiar?

From: “Technology Solutions for the collection of patient reported outcomes data”.  Bill Byrom. European Pharmaceutical Contractor, 2004.

confidential

benefits of epro
Benefits of ePRO
  • Who hasn’t had a paper diary nightmare?
  • Process benefits on the theme of cleaner data quicker
    • More complete – high compliance
    • Improved integrity – date:time stamps
    • Increased consistency – logic checks
    • No free or extraneous text
    • Automatically coded
  • Don’t forget better science - far greater compliance with protocol
    • Who’d want to defend paper diary data to a regulator?

confidential

nci invivodata diary methods study stone et al 2002 british medical journal

Instrumented Paper Diary*

N = 40

invivodata eDiary†

N = 40

*Contained hidden

photosensor

†Actual eDiary used

in 2002 Study

NCI & invivodata Diary Methods Study Stone et al. (2002): British Medical Journal

eDiary v Paper

confidential

results ediary vs paper diary stone et al 2002 british medical journal

100

80

60

40

20

0

% Compliance

Paper eDiary

Reported compliance

Actual compliance

Results: eDiary vs. Paper Diary Stone et al. (2002): British Medical Journal

eDiary v Paper

  • Paper Compliance
    • Reported: 90%
    • Actual: 11%
  • eDiary Compliance
    • Reported: 94%
    • Actual: 94%

confidential

obstacles and overcoming them
Obstacles and overcoming them
  • Fear of change
    • We’ve always done it this way
    • Precedent not acceptable to regulators

confidential

obstacles and overcoming them1
Obstacles and overcoming them
  • Lack of awareness of modern ePRO
    • No longer something like this….
    • Or this….

confidential

more obstacles
More obstacles
  • Not enough time?
    • Not enough time for what?
    • Not enough time to plan for success = planning for failure
  • Sites won’t like it?
    • Where’s the evidence for this?
    • Who pays them?
    • Doesn’t stop us using EDC widely

confidential

pro scale migration
PRO Scale Migration
  • Consensus has emerged on best practice
  • Documented by ISPOR “PRO Good Research Practices Task Force”
  • Published in Value in Health
    • Coons et al, 1098-3015/08
    • “Recommendations on Evidence Needed to Support Measurement Equivalence between Electronic and Paper-Based Patient-Reported Outcome (PRO) Measures: ISPOR ePRO Good Research Practices Task Force Report”

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levels of modification
Levels of Modification

Adapted from Shields et al.

confidential

examples of modification
Examples of Modification

Adapted from Shields et al.

confidential

evidence required
Evidence Required

Adapted from Shields et al.

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patients can t use it
Patients can’t use it?
  • Severe Parkinson’s Disease patient

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emerging best practice
Emerging Best Practice
  • PRO Strategy
    • PRO Dossier
    • PRO input into protocol
    • An Endpoint Development Process

confidential

begin with the end in mind
“Begin with the end in mind”

Labeling Claims

Disease/Conceptual Model

Measurement Strategy

Instruments/Items

Conceptual Framework

Endpoint Model

Endpoints

confidential

a few words on instruments
A Few Words on Instruments
  • When is a PRO instrument adequate to support labeling claims?
    • “The adequacy of a PRO instrument as a measure to support medical product labeling claims depends on its documented measurement properties that demonstrate the instrument is ‘fit for purpose’” (Burke, 2008).
      • “Fit for purpose” means that the instrument is specific to and defined by the patient population and the specified disease, treatment, and selected endpoints.
    • In this circumstance, “instrument is defined as a means to capture data (i.e., a questionnaire) plus all the information and documentation that supports its use” (Burke, 2008).

confidential

impact of fda pro guidance
Impact of FDA PRO Guidance
  • Study Endpoints and Labeling Division (SEALD) are reviewing programs where labeling claims based upon PRO
  • Feedback from FDA specifically cites PRO Guidance
  • Expectations for PRO activity and documentation being driven by Guidance
  • PRO Submission/dossier template
  • Created a need for practical resources to better understand the nature of PROs
    • best practices that facilitate the effective development of PRO instruments.

confidential

common pitfalls myths
Common Pitfalls/Myths
  • We can go at risk and then just ask the FDA after-the-fact
  • Lack of patient-interview based data
    • Needed to support the importance and relevance of the concepts and items in the PRO instrument
  • The instrument is ‘valid’ in patient population A, therefore it is OK to use in patient population B
  • We can wait until Ph III to address the PRO instrument issues

confidential

endpoint development process

Ongoing Synthesis of Material

Conceptual

Model

Development

Concept

Justification

Measurement

Strategy

Instrument

Identification

Conceptual

Framework

Endpoint

Model

Endpoint Development Process
  • A tool for meeting scientific and regulatory needs

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endpoint development process1
Endpoint Development Process

Ongoing Synthesis of Material

Conceptual

Model

Development

Concept

Justification

Measurement

Strategy

Instrument

Identification

Conceptual

Framework

Endpoint

Model

Identify

Program

Goals & Claims

Expert

Input

Focus of

Assessment

Identify Existing

Instruments

Theoretical

Validation

Evidence/Plan

Study

Design

Requirements

Identify

Relevant

Population

Patient

Reports

Interval of

Assessment

Modify Existing

Instruments

Psychometric

Validation

Evidence/Plan

Construction

of

Endpoints

Identify

Relevant

Drug Effects

Empirical

Evidence

Recall

Period

Identify

Alternate

Measurement

Strategies

Identify

Relevant

PRO Concepts

Timing &

Schedule of

Assessment

Develop Novel

Instruments

confidential

conceptual model specifying substantiating concepts
Conceptual Model: Specifying & Substantiating Concepts

Signs/

Symptoms

General

Impact

Disease

Related

Impact

Drug Action

Concept Justification

Impact 1A

Patient

Population

Relevant

Disease

Process

  • Signs
  • Symptoms

Impact 2A

Impact 1B

Diagnosis

confidential

concept justification
Concept Justification

Yes indicates that this justification criterion has been satisfied

No indicates that this justification criterion has not yet been satisfied

TBD indicates To Be Determined

confidential

conceptual framework
Conceptual Framework

PRO Concept

Item 1

Item 2

PRO Concept

Label Claim

Item 3

PRO Concept

Item 4

Item 5

Label Claim

PRO Concept

Item 6

confidential

pro strategy pointers
PRO Strategy Pointers
  • Begin thinking of PRO strategy early in development
  • Interact with regulators
  • PRO EDP provides structure for elements of PRO Strategy and Dossier
  • Think about preparation for trial implementation

confidential

what about epro design
What about ePRO Design
  • ePRO Solution Design
    • Maximise value of new modalities
      • Don’t simply recreate the weaknesses of paper instruments
    • Less missing data
    • More precise measures
    • More frequent, reliable measures

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fda s view on pro design

(Federal Register, Vol. 71, No. 23; Feb. 3, 2006)

FDA’s view on PRO Design

“PRO instruments that require patients to rely on memory … may threaten the accuracy of the PRO data. It is usually better to construct items that ask patients to describe their current state than to ask them to compare their current state with an earlier period or to attempt to average their experiences over a period of time.”

(Pg. 11; 339-343 – emphasis added)

confidential

what about1
What about…?
  • Psychometric validation
    • Luckily the FDA have written us an abridged text book on psychometrics
    • It’s called the FDA PRO Guidance
    • Applies to paper as well
    • Eliciting the patient perspective is a central tenet

confidential

psychometric validation
Psychometric Validation
  • Large proportion of the FDA PRO Guidance refers to psychometric aspects
  • With any PRO you need to show evidence that:
    • “The adequacy of a PRO instrument as a measure to support medical claims depends on its development history and demonstrated measurement properties”
    • Reliability
    • Validity
    • Ability to detect change
    • Interpretability
  • A specialised area that applies as much to paper as electronic

confidential

what about linguistic validation
What about Linguistic Validation?
  • Translations (to a high standard)
    • Full title: linguistic validation & cultural adaptation
  • Best practice well established
  • Plenty of vendors to choose from
  • Timelines typically 8 – 11 weeks
  • Applies to paper as well

confidential

scientific improvements
Scientific Improvements
  • Patients are answering questions at the time of clinical interest
    • In other words as specified in the protocol and not just before a clinic visit
  • Patients give more complete answer sets so improving statistical power (ref: ACT 2004)
  • ePRO allows more sophisticated and targeted questioning
  • Competing compounds are now likely to be using ePRO
    • Who wants to be seen using inferior methods.

confidential

regulatory motives
Regulatory Motives
  • EMA and FDA regularly accept ePRO data for primary and secondary endpoints.
    • This is not something they view with suspicion.
  • Recently BfArM (the German regulatory authority) explicitly directed a sponsor to use ePRO rather than paper
  • The FDA PRO Guidance sets out clear expectations for the use of any form of PROs (paper or electronic)
    • http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM193282.pdf

confidential

thank you

Thank You

Adam Wood

e: awood@invivodata.com

 +44 78 5492 8430